cells Review TRPC Channels in Proteinuric Kidney Diseases Gentzon Hall, Liming Wang and Robert F. Spurney * Division of Nephrology, Department of Medicine, Duke University; Durham, NC 27710, USA; [email protected] (G.H.); [email protected] (L.W.) * Correspondence: [email protected]; Tel.: +1-919-684-9729 Received: 18 November 2019; Accepted: 19 December 2019; Published: 23 December 2019 Abstract: Over a decade ago, mutations in the gene encoding TRPC6 (transient receptor potential cation channel, subfamily C, member 6) were linked to development of familial forms of nephrosis. Since this discovery, TRPC6 has been implicated in the pathophysiology of non-genetic forms of kidney disease including focal segmental glomerulosclerosis (FSGS), diabetic nephropathy, immune-mediated kidney diseases, and renal fibrosis. On the basis of these findings, TRPC6 has become an important target for the development of therapeutic agents to treat diverse kidney diseases. Although TRPC6 has been a major focus for drug discovery, more recent studies suggest that other TRPC family members play a role in the pathogenesis of glomerular disease processes and chronic kidney disease (CKD). This review highlights the data implicating TRPC6 and other TRPC family members in both genetic and non-genetic forms of kidney disease, focusing on TRPC3, TRPC5, and TRPC6 in a cell type (glomerular podocytes) that plays a key role in proteinuric kidney diseases. Keywords: transient receptor potential cation channel; transient receptor potential canonical channel; TRPC channel; focal segmental glomerulosclerosis; diabetic kidney disease; diabetic nephropathy; chronic kidney disease; TRPC6; TRPC5; TRPC3 1. The Burden of Chronic Kidney Disease (CKD) CKD is a public health problem that affects more than 20 million Americans in the United States [1]. The disease is caused by a diverse group of primary, secondary, and genetic disorders that impair the ability of the kidney to remove waste, regulate intravascular volume, reclaim essential nutrients, and stimulate erythropoiesis [2]. As the disease progresses, these essential functions become increasingly impaired, eventually leading to end-stage kidney disease (ESKD). Of the 20 ≈ million Americans with CKD, almost 600,000 have irreversible kidney failure and require either renal transplantation or dialysis to sustain life [3]. The expense of providing ESKD care to this patient population costs 50 billion dollars per year in the United States [3]. Moreover, morbidity and mortality ≈ are markedly increased in CKD patients with lesser degrees of renal impairment, which is largely caused by an increased risk of cardiovascular events as renal function declines [1,4]. Although current treatments for CKD may slow disease progression, many patients progress to more advanced stages of CKD, and ESKD, despite available therapies [2]. As a result, there is a significant interest in developing new treatment approaches. 2. The Glomerular Podocyte Plays a Key Role in Proteinuric Kidney Diseases Podocytes are highly differentiated, postmitotic cells that play a critical role in maintaining the integrity of the glomerular filtration barrier [5]. As shown in Figure1A,B, their interdigitating foot processes (FPs) cover the exterior surface of the glomerular basement membrane (GBM), and form a specialized intercellular junction between adjacent FPs known as the slit diaphragm (SD) [6]. The SD is a sieve-like, size-selective filtration barrier, which prevents loss of cells and macromolecules into the Cells 2020, 9, 44; doi:10.3390/cells9010044 www.mdpi.com/journal/cells Cells 2020, 9, 44 2 of 24 glomerular ultrafiltrate [7,8]. It is composed of proteins commonly found in tight and adherens junctions such asCells P-cadherin, 2019, 8, x zonula occludens-1 (ZO-1), and catenin family members, as well as proteins2 of 24 predominantly expressed in podocytes including nephrin, neph1, and podocin [7,8]. Both nephrin and neph1junctions are members such as P- ofcadherin, the immunoglobulin zonula occludens (Ig)-1 (ZO superfamily-1), and catenin [7]. Theirfamily extracellular members, as domainswell as containproteins multiple predominantly IgG-like motifs, expressed which in can podocytes aggregate including and form nephrin, zipper-like neph1, structuresand podocin that [7,8 surround]. Both the glomerularnephrin capillaries,and neph1 are creating members a sieve-like of the immunoglobulin filtration barrier. (Ig) Both superfamily nephrin [7] and. Their neph1 extracellular also have a domains contain multiple IgG-like motifs, which can aggregate and form zipper-like structures that single transmembrane domain and a short intracellular carboxy-terminus, which serves as a scaffold surround the glomerular capillaries, creating a sieve-like filtration barrier. Both nephrin and neph1 for assembling signaling complexes with other podocyte proteins such as CD2AP (CD2-associated also have a single transmembrane domain and a short intracellular carboxy-terminus, which serves protein)as and a scaffold podocin for assembling [8,9]. The signaling carboxy-terminus complexes ofwith nephrin other podocyte has conserved proteins such tyrosine as CD2AP residues (CD2 that- can be phosphorylatedassociated protein) by and Src podocin family kinases[8,9]. The [7 ,10carboxy–13].- Phosphorylatedterminus of nephrin nephrin has conserved recruits additionaltyrosine signalingresidues molecules that can to thebe phosphorylated scaffolding complex by Src family that, in kinases turn, influence[7,10–13]. Phosphorylated multiple downstream nephrin recruits signaling pathwaysadditional and modulate signaling cytoskeletal molecules reorganization,to the scaffolding cellular complex survival, that, membranein turn, influence trafficking, multiple cellular adhesion,downstream and mechano-signaling signaling pathways [7,10 ,14and,15 ].modulate cytoskeletal reorganization, cellular survival, membrane trafficking, cellular adhesion, and mechano-signaling [7,10,14,15]. Figure 1. Glomerular ultrastructure and TRPC family members. (A) An electron micrograph of Figure 1. Glomerular ultrastructure and TRPC family members. (A) An electron micrograph of glomerular ultrastructure is presented. The podocyte cell body is located in the urinary space on glomerular ultrastructure is presented. The podocyte cell body is located in the urinary space on the the outerouter surface surface of theof the glomerular glomerular basement basement membrane (GBM). (GBM). Primary Primary processes processes extend extend from fromthe cell the cell bodybody and and branch branch into into interdigitating interdigitating foot foot processes processes (FPs) (FPs) that that cover cover the external the external surface surface to the GBM to the GBM (black(black arrow arrow heads)heads) to to form form filtration filtration slits slits and and the specialized the specialized intercellular intercellular junction junction termed the termed slit the slit diaphragmdiaphragm (SD). (SD). The The glomerular glomerular filter filter is composed is composed of the ofpodocyte the podocyte FPs with FPs the withintervening the intervening SDs, the SDs, theGBM GBM (black (black arrow arrow heads) heads),, and anda fenestrated a fenestrated endothelium endothelium (white arrowheads) (white arrowheads) that lines the that capillary lines the capillaryloops. loops. (B ()B )This This high high power power view view shows shows the the three three layers layers of of the the glomerular glomerular filter filter including including the the fenestratedfenestrated endothelium endothelium (white (white arrowheads), arrowheads), GBM GBM (black (black arrowheads), arrowheads), andand the FPs FPs (white (white arrows) arrows) with thewith interposed the interposed filtration filtration slits (black slits (black arrows). arrows An). An asterisk asterisk indicates indicates a a primary primary process (also (also termed termed a major process). (C) The phylogenetic tree of TRP family members is shown in panel C. The a major process). (C) The phylogenetic tree of TRP family members is shown in panel C. The vertebrate vertebrate TRPC family has seven members, which are divided into four subgroups: TRPC1, TRPC2, TRPC family has seven members, which are divided into four subgroups: TRPC1, TRPC2, TRPC4/5, TRPC4/5, and TRPC3/6/7. The figure shows the relationship between TRPC family members and and TRPC3other/6 /members7. The figure of the shows TRP family. the relationship In humans, betweenTRPC2 is TRPCa pseudogene family (see members text). and other members of the TRP family. In humans, TRPC2 is a pseudogene (see text). Cells 2020, 9, 44 3 of 24 In addition to their role in forming a size selective filtration barrier, podocytes stabilize the glomerular architecture by counteracting the elastic forces distending the GBM [6]. Indeed, the hydraulic pressure within glomerular capillaries is unusually high compared to other capillary beds [16]. It is estimated that podocytes are responsible for approximately 40% of the hydraulic resistance of the filtration barrier [6]. Moreover, accumulating evidence suggests that dynamic signaling between the SD and focal adhesions may promote both podocyte adherence to the GBM and maintenance of glomerular filtration barrier function [7,17,18]. In support of this hypothesis, lamellipodia formation at focal adhesions are necessary for cell migration and are induced downstream of nephrin phosphorylation in cultured podocytes [19,20]; conversely, β1 integrin activation induces tyrosine phosphorylation of nephrin [21].